Sarcopenia is the reduction in muscle mass that occurs with aging. It is a progressive process that occurs throughout adult life such that by the time a person reaches 80 years of age his or her muscle mass may have declined by as much as 50% from their prime of life in the late teens to early twenties. This reduction of muscle mass is a significant factor in the development of frailty, which is accompanied by falls that lead to fractures and ultimately to morbidity and mortality. Sarcopenia is believed to be associated with metabolic, physiologic, and functional impairments and disability. There are no simple treatments available to prevent it.
Baumgartner et al. (Am J Epidemiol 1998; 147:755-63; 149: 1161) have defined sarcopenia as appendicular skeletal muscle mass (kg/height2 (m2)) being less than two standard deviations below the mean of a young reference group. This is referred to as a “t-score” hereinafter. Baumgartner et al used the data from the New Mexico Elder Health Survey, 1993-1995 to develop a method for estimating the prevalence of sarcopenia and found that the prevalence “increased from 13-24% in persons under 70 years of age to >50% in persons over 80 years of age[.]” The study by Baumgartner et al was one of the first to estimate the extent of the prevalence of sarcopenia.
The physiological mechanism for the decline in muscle mass is unknown. Growth hormone secretion declines progressively from mid puberty, and growth hormone is known to increase muscle mass. Patients with growth hormone deficiency have reduced muscle mass and increased fat mass. Growth hormone replacement increases the muscle mass and leads to a reduction in fat mass.
Growth hormone secretagogues have been developed to enhance growth hormone secretion. A growth hormone secretagogue is a compound that, when administered to a patient, increases the production and/or secretion of growth hormone when compared with baseline plasma concentrations of growth hormone in a normal healthy individual. They act through a growth hormone secretagogue receptor. A natural ligand for this receptor was discovered in 1999, and it is produced in the mucosa of the stomach. It is called ghrelin and has a unique modification at serine in position 3. The modification is that it is N-octonylated.
Ibutamoren mesylate (MK-677) was developed at Merck Research Laboratories as a specific orally active growth hormone secretagogue. Journal of Orthopaedic Research 15:519:527 (1997) states that a growth hormone secretagogue, MK-677, elevated levels of serum insulin-like growth factor-1, which in turn increased the size and strength of the quadriceps muscle in canines during remobilization. J. Clin. Endocrinol. Metab. 83: 320-325, 1998, states that MK-677, an orally active growth hormone secretagogue, reverses diet-induced catabolism.
U.S. Pat. No. 6,194,402 (Bach et al) describes the use of growth hormone secretagogues, including MK-677, for “enhancing the return of a patient to independent living status following acute deconditioning of [a ] patient who was living independently prior to such acute deconditioning[.]” (See claim 1.) Bach et al define the term ‘acute deconditioning’ to indicate the presence of a diminished state in a patient characterized by muscle atrophy and muscle loss which results from specific insult such as immobilization or inactivity brought on by acute illness or injury. In contrast, chronic deconditioning is defined as long-term muscle loss or wasting, i.e., sarcopenia.
Bach et al clearly distinguish between acute deconditioning and sarcopenia. This is because the maintenance of muscle mass depends on two different processes: maintaining function and exercise that allow muscle mass to be maintained or built; and, an ability to maintain muscle mass that depends on nutrition, neural input, and hormonal state. The peak muscle mass is observed at the time of mid-puberty and muscle mass progressively declines and is detectably reduced by the age of 45 years and continues to progressively decline. This decline in muscle mass appears to be dependent on growth hormone secretion, which declines with age. Even Olympic athletes lose muscle mass and function as they age despite regular exercise.
US Patent Publication No. 2002/0028838 (MacLean et al) recites a “[m]ethod for treating age related decline in physical performance in an at-risk patient which comprises administering to the patient a performance enhancing effective amount of a growth hormone secretagogue.” (See claim 1.) MacLean et al state that “[t]he term ‘at-risk patient’ is a patient who exhibits objective evidence of decline in physical performance as measured by established methods of physical performance assessment. Measures of physical performance are objective tests of subjects' performance of standardized tasks, evaluated according to predetermined criteria that may include counting repetitions or timed activity. A decline in physical performance results in increased odds of the patient suffering an adverse event such as an injurious fall and/or fracture. A decline in physical performance may also result in the patient having to be admitted to a nursing home and/or developing functional dependence in activities of daily living.” (See paragraph 0173.) This population and this condition are distinct and separate from the population suffering from and the indication of sarcopenia because sarcopenia occurs prior to the development of decline in physical performance. The treatment of sarcopenia is not considered by MacLean et al as this indication occurs long before a patient would be considered “at-risk” by MacLean et al.
In view of the substantially increasing age of the population in developed nations and the inevitability of sarcopenia, it is highly desirable to find a method for treating sarcopenia.